The Effects of Bisphosphonates Used in Osteoporosis Treatment on Breast Cancer: Analysis with Integrative Bioinformatics Methods, DFT, ADMET and Molecular Docking Analysis
Abstract
This study evaluated the structural, electronic, pharmacokinetic, and receptor-binding properties of three bisphosphonate derivatives, alendronate, risedronate, and zoledronate, to investigate their therapeutic relevance in osteoporosis and breast cancer. Density Functional Theory (DFT) calculations at the B3LYP/6-31G(d,p) level showed that risedronate exhibited the highest kinetic stability (ΔE = 6.7468 eV), whereas zoledronate displayed greater chemical reactivity (ΔE = 2.9669 eV) and the strongest nonlinear optical response (β = 1.20 × 10<sup>-30</sup> esu). ADMET analysis indicated acceptable safety profiles for all compounds, although high polarity and low lipophilicity may limit oral bioavailability. Molecular docking against 11 breast cancer- and bone metabolism-related targets revealed favorable binding affinities, particularly for zoledronate and risedronate. Zoledronate showed strong interactions with <i>ESR2</i>, <i>VEGFR</i>/<i>KDR</i>, <i>GGPS1</i>, and <i>FPPS</i>, whereas risedronate exhibited notable affinity for <i>BRCA2</i> and <i>MMP9</i>. Bioinformatics analyses identified significant dysregulation of <i>GGPS1</i>, <i>FDPS</i>, <i>TNFSF11</i>, <i>ESR1</i>, <i>MMP9</i>, and <i>BRCA2</i> in breast cancer tissues, while survival analysis linked elevated FDPS, <i>MMP9</i>, and <i>BRCA2</i> expression to poor prognosis. Network analyses highlighted pathways related to mevalonate metabolism, hormone signaling, angiogenesis, extracellular matrix remodeling, and the <i>RANK</i>/<i>RANKL</i>/<i>OPG</i> axis. These findings support the potential repurposing of bisphosphonates, particularly zoledronate, for breast cancer-associated bone disease.